Registry randomised trials: a methodological perspective.

Registry randomised clinical trials (RRCTs) have the potential to provide pragmatic answers to important clinical questions. RRCTs can be embedded into large population-based registries or smaller single site registries to provide timely answers at a reduced cost compared with traditional randomised controlled trials. RRCTs can take a number of forms in addition to the traditional individual-level randomised trial, including parallel group trials, platform or adaptive trials, cluster randomised trials and cluster randomised stepped-wedge trials. From an implementation perspective, initially it is advantageous to embed RRCT into well-established registries as these have typically already overcome any issues with end point validation and adjudication. With advances in data linkage and data quality, RRCTs can play an important role in answering clinical questions in a pragmatic, cost-effective way.

Constant-moderate versus high-intensity interval training on heart adiponectin levels in high-fat fed mice: a preventive and treatment approach.

CONTEXT: Research has described that adiponectin plays a key role in cardiomyocytes metabolism, however, the effects of exercise during obesity on cardiac adiponectin levels is unclear. OBJECTIVE: To investigate the effects of constant-moderate endurance (END) and high-intensity interval training (HIIT), on heart adiponectin levels in mice. MATERIAL AND METHODS: Two experiments were conducted: (1) preventive (EX1): 10 week-old male mice were fed standard (CHOW) or high-fat diet (HFD;45% fat) and simultaneously trained with END and HIIT for 10 weeks; (2) Treatment (EX2): after 10 weeks of dietary intervention, another cohort of 10 week-old mice were trained by both programmes for 10 weeks. RESULTS: In EX1, END and HIIT decreased low-molecular weight adiponectin (∼0.5-fold; p < 0.05) and increased GLUT4 levels (∼2-fold; p < .05). In EX2, HFD significantly decreased high-molecular weight adiponectin (∼0.7-fold; p < .05), and END reversed this change.Discussion and conclusion: HFD and exercise influence heart adiponectin isoforms and therefore might impact cardiomyocyte metabolism.

A framework for de-identification of free-text data in electronic medical records enabling secondary use.

Clinical free-text data represent a vast, untapped source of rich information. If more accessible for research it would supplement information captured in structured fields. Data need to be de-identified prior to being reused for research. However, a lack of transparency with existing de-identification software tools makes it difficult for data custodians to assess potential risks associated with the release of de-identified clinical free-text data. This case study describes the development of a framework for releasing de-identified clinical free-text data in two local health districts in NSW, Australia. A sample of clinical documents (n = 14 768 965), including progress notes, nursing and medical assessments and discharge summaries, were used for development. An algorithm was designed to identify and mask patient names without damaging data utility. For each note, the algorithm output the (i) note length before and after de-identification, (ii) the number of patient names and (iii) the number of common words. These outputs were used to iteratively refine the algorithm performance. This was followed by manual review of a random subset of records by a health information manager. Notes that were not correctly de-identified were fixed, and performance was reassessed until resolution. All notes in this sample were suitably de-identified using this method. Developing a transparent method for de-identifying clinical free-text data enables informed-decision making by data custodians and the safe re-use of clinical free-text data for research and public benefit.

Effects of aerobic exercise on fibroblast growth factor 21 in overweight and obesity. A systematic review.

Fibroblast growth factor 21 (FGF21) has been suggested to improve metabolism during aerobic exercise in obesity. However, the variability of exercise interventions gives rise to discrepancies in the field. Therefore, we aimed to systematically review the available literature regarding the effects of aerobic exercise on FGF21 in the context of overweight and obesity. Our search included original articles published between 2009 and November 2021 found in PubMed, Science Direct, and Medline. Clinical and preclinical studies were included. Studies, where subjects or animals presented with other conditions (e.g., cancer, stroke), were excluded. From an initial 43 studies, 19 (clinical studies = 9; preclinical studies = 10) were eligible for inclusion in this review. The main findings were that acute exercise tended to increase circulatory levels of FGF21. In contrast, chronic exercise programs (≥4 weeks) had the opposite effect along with inducing mRNA and protein increases of FGF receptors and ß-klotho in adipose tissue, liver, and skeletal muscle. In conclusion, both clinical and preclinical studies showed that aerobic exercise exerts changes in circulatory and tissue FGF21, along with its receptors and co-receptor. Future research is needed to elucidate the mechanisms, along with the physiological and clinical implications of these changes.

Combining structured and unstructured data in EMRs to create clinically-defined EMR-derived cohorts.

BACKGROUND: There have been few studies describing how production EMR systems can be systematically queried to identify clinically-defined populations and limited studies utilising free-text in this process. The aim of this study is to provide a generalisable methodology for constructing clinically-defined EMR-derived patient cohorts using structured and unstructured data in EMRs. METHODS: Patients with possible acute coronary syndrome (ACS) were used as an exemplar. Cardiologists defined clinical criteria for patients presenting with possible ACS. These were mapped to data tables within the production EMR system creating seven inclusion criteria comprised of structured data fields (orders and investigations, procedures, scanned electrocardiogram (ECG) images, and diagnostic codes) and unstructured clinical documentation. Data were extracted from two local health districts (LHD) in Sydney, Australia. Outcome measures included examination of the relative contribution of individual inclusion criteria to the identification of eligible encounters, comparisons between inclusion criterion and evaluation of consistency of data extracts across years and LHDs. RESULTS: Among 802,742 encounters in a 5 year dataset (1/1/13-30/12/17), the presence of an ECG image (54.8% of encounters) and symptoms and keywords in clinical documentation (41.4-64.0%) were used most often to identify presentations of possible ACS. Orders and investigations (27.3%) and procedures (1.4%), were less often present for identified presentations. Relevant ICD-10/SNOMED CT codes were present for 3.7% of identified encounters. Similar trends were seen when the two LHDs were examined separately, and across years. CONCLUSIONS: Clinically-defined EMR-derived cohorts combining structured and unstructured data during cohort identification is a necessary prerequisite for critical validation work required for development of real-time clinical decision support and learning health systems.

Mechanism for the Increase in Human Growth Hormone with Administration of a Novel Test Supplement and Results Indicating Improved Physical Fitness and Sleep Efficiency.

An oral test supplement increases serum human growth hormone (hGH) levels after acute administration in healthy adults. We investigated the mechanism for the increase in hGH and the effect of continued daily administration of the test supplement on measures of physical fitness and sleep efficiency. In Study 1, serum triiodothyronine (T3) was measured in samples from a prior placebo-controlled, double-blind study in which 16 healthy participants received both placebo and the test supplement in a crossover design; treatment order was randomized, and treatments were separated by a 1-week washout. In Study 2, physical fitness (VO2 max) was measured at baseline and after 2 weeks of daily administration of the test supplement (N = 12 healthy participants). Study 3 assessed daily sleep onset latency and time awake during 3 weeks of daily administration of the test supplement (N = 15 healthy participants). A fall from baseline in T3 was observed with placebo (-6.1 ± 8.5 ng/dL, P = .01). Of note, the change in T3 was smaller with the test supplement (-3.3 ± 10.7 ng/dL, P = not significant) but was not statistically different from placebo. Mean VO2 max increased by 6% from baseline after 2 weeks (P = .02). Sleep-onset latency and time awake during the night were reduced from baseline to week 3 by 22% and 65%, respectively (P = .01 and P = .02). The conservation of T3 levels suggests that the mechanism for increased hGH secretion by the test supplement is through somatostatin inhibition. Furthermore, pilot studies indicated that daily administration of the supplement improved physical fitness and sleep efficiency from baseline, effects consistent with increased endogenous hGH release. Clinical Trial Registration No. NCT02987868.

Assessment of insulin sensitivity during hyperbaric oxygen treatment.

INTRODUCTION: Previous studies using a hyperinsulinaemic, euglycaemic glucose clamp have demonstrated an increase in peripheral insulin sensitivity in men with and without Type-2 diabetes mellitus on the third and thirtieth hyperbaric oxygen treatment (HBOT) session. In two studies using different techniques for assessment of insulin sensitivity, we investigated the onset and duration of this insulin-sensitising effect of HBOT. METHODS: Men who were obese or overweight but without diabetes were recruited. One study performed a hyperinsulinaemic euglycaemic glucose clamp (80 mU.m-2.min-1) at baseline and during the first HBOT exposure (n = 9) at a pressure of 203 kPa. Data were analysed by paired t-test. The other study assessed insulin sensitivity by a frequently sampled intravenous glucose tolerance test (FSIGT) at three time points: baseline, during the third HBOT and 24-hours post-HBOT (n = 9). Results were analysed by repeated-measures ANOVA. RESULTS: There was a significant 23% increase in insulin sensitivity by clamp measured during the first HBOT exposure. The FSIGT showed no significant changes in insulin sensitivity. CONCLUSIONS: The hyperinsulinaemic, euglycaemic glucose clamp demonstrated a significant increase in peripheral insulin sensitivity during a single, 2-hour HBOT session in a group of men who were obese or overweight but without diabetes. As an alternate technique for assessing insulin sensitivity during HBOT, the FSIGT failed to show any changes during the third HBOT and 24-hours later, however modification of the study protocol should be considered.

Increased Human Growth Hormone After Oral Consumption of an Amino Acid Supplement: Results of a Randomized, Placebo-Controlled, Double-Blind, Crossover Study in Healthy Subjects.

BACKGROUND: Human growth hormone (hGH) is best known for influencing bone and muscle growth, as well as body composition, but the use of recombinant hGH is controversial. Amino acids are a potentially safer alternative; however, preliminary investigations of the effects of oral amino acids on hGH release have been inconclusive. Therefore, we tested the effects of a novel blend of amino acids optimized to increase hGH release. STUDY QUESTION: Does an investigational amino acid supplement affect hGH release? STUDY DESIGN: This was a randomized, placebo-controlled, double-blind, crossover study that included 16 (12 men, 4 women; age 32 ± 14 years; body mass index 26.4 ± 5.0 kg/m) healthy participants. All participants received both placebo and the amino acid supplement after an overnight fast and completed all study visits. Treatment order was randomized, and each treatment was separated by a 1-week washout period. MEASURES AND OUTCOMES: The primary outcomes were the percent change in hGH from baseline to 120 minutes and the area under the curve of hGH over baseline. Serum hGH was measured using enzyme-linked immunosorbent assay at baseline and 15, 30, 60, 90, and 120 minutes. RESULTS: At 120 minutes, hGH levels increased by 682% (8-fold) from baseline and were significantly higher than placebo (P = 0.01). In addition, a significantly higher mean area under the curve was observed for the amino acid supplement compared with the placebo [20.4 (95% confidence interval, 19.9-21.0 ng/mL) vs. 19.7 (95% confidence interval, 18.7-20.6 ng/mL); P = 0.04]. CONCLUSIONS: These results show that a single dose of the oral amino acid supplement was sufficient to significantly increase hGH levels in healthy adult men and women. CLINICAL TRIAL REGISTRY:: clinicaltrials.gov NCT01540773.

Skeletal muscle adiponectin induction in obesity and exercise.

Recent scientific efforts have focused on the detrimental effects that obesity has on the metabolic function of skeletal muscles and whether exercise can improve this dysfunction. In this regard, adiponectin, with important metabolic functions (e.g. insulin-sensitizer and anti-inflammatory), has been recently described as a myokine that acts in an autocrine/paracrine manner. Earlier studies reported that muscle adiponectin could be induced by pro-inflammatory mediators (e.g. lipopolysaccharide), cytokines, and high-fat diets, providing a protective mechanism of this tissue against metabolic insults. However, when metabolic insults such as high-fat diets are sustained this protective response becomes dysregulated, making the skeletal muscle susceptible to metabolic impairments. Recent studies have suggested that exercise could prevent or even reverse this process. Considering that most scientific knowledge on adiponectin dysregulation in obesity is from the study of adipose tissue, the present review summarizes and discusses the literature available to date regarding the effects of obesity on skeletal muscle adiponectin induction, along with the potential effects of different exercise prescriptions on this response in an obesity context.

Constant-Moderate and High-Intensity Interval Training Have Differential Benefits on Insulin Sensitive Tissues in High-Fat Fed Mice.

In a mouse model of diet-induced obesity, this study determined if two exercise prescriptions with equivalent time and distance covered, [constant-moderate endurance (END) and high intensity interval training (HIIT)], exert differential metabolic benefits on insulin sensitive tissues. Male 10 week old C57BL/6 mice were fed a high fat diet (HFD; 45% kcal fat) ad libitum for 10 weeks and for a further 10 weeks they underwent END or HIIT training (3 × 40 min sessions/wk). Untrained HFD and chow-fed mice acted as controls. At 30 weeks of age, mice were sacrificed and quadriceps muscle, subcutaneous adipose tissue (SAT) and liver were excised. Neither END nor HIIT altered body weight or composition in HFD mice. In quadriceps, HFD decreased high-molecular weight adiponectin protein, which was normalized by END and HIIT. In contrast, HIIT but not END reversed the HFD-driven decrease in the adiponectin receptor 1 (AdipoR1). In SAT, both programs tended to decrease collagen VI protein (p = 0.07-0.08) in HFD, whereas only HIIT induced an increase in the mRNA (3-fold vs. HFD untrained) and protein (2-fold vs. HFD untrained) of UCP1. In liver, only END reversed collagen I accumulation seen in HFD untrained mice. Our results suggest that HIIT may promote better systemic metabolic changes, compared to END, which may be the result of the normalization of muscle AdipoR1 and increased UCP1 seen in SAT. However, END was more effective in normalizing liver changes, suggesting differential metabolic effects of END and HIIT in different tissues during obesity.

Metabolic inflexibility in women with PCOS is similar to women with type 2 diabetes.

BACKGROUND: An ability to switch between primarily oxidizing fat in the fasted state to carbohydrate in the fed state, termed metabolic flexibility, is associated with insulin sensitivity. Metabolic flexibility has been explored previously in women with polycystic ovary syndrome (PCOS), yet the independent or synergistic contributions of androgen excess and/or insulin resistance is not yet known. Therefore, the purpose of this article was to characterize metabolic flexibility in women with PCOS compared to women of normal BMI, obesity, or type 2 diabetes (T2DM). METHODS: Eighty-six weight-stable women; thirty with either PCOS (n = 30), or fifty-six with obesity (n = 12), T2DM (n = 27), or normal BMI (n = 17) underwent a hyperinsulinemic euglycemic clamp and indirect calorimetry to measure insulin sensitivity and substrate oxidation via indirect calorimetry, respectively. RESULTS: All analyses were adjusted for differences in age, ethnicity, and BMI between groups. Women with PCOS were less metabolically flexible compared to healthy women with obesity (p < 0.0001), normal BMI (p < 0.0001), but after controlling for glucose disposal rate, were similar to women with T2DM (p = 0.99). When dividing women with PCOS above and below the mean cutoff for insulin resistance, the insulin resistant women with PCOS had lower rates of non-oxidative glucose metabolism (p = 0.0001), higher levels of percent free testosterone (p = 0.04), a higher free androgen index (p = 0.006), more visceral adipose tissue (p = 0.02), and were less metabolically flexible (p = 0.007). CONCLUSIONS: Women with T2DM were as metabolically inflexible as women with PCOS. When stratifying women with PCOS into those who are metabolically flexible and inflexible, the women who are inflexible display greater amounts of visceral fat and androgen excess. The inability to alter substrate use given the physiological stimulus may lead to subsequent increases in adiposity in women with PCOS thereby further worsening the insulin resistance. TRIAL REGISTRATION NUMBER: Clinical Trials.gov, NCT01482286. Registered 30 November 2011.

Skeletal muscle adiponectin induction depends on diet, muscle type/activity, and exercise modality in C57BL/6 mice.

Changes in skeletal muscle adiponectin induction have been described in obesity and exercise. However, whether changes are consistent across muscle types and with different exercise modalities, remain unclear. This study compared the effects of diet and two isocaloric training programs on adiponectin induction and its regulators in three muscles: quadriceps (exercising/glycolytic-oxidative), gastrocnemius (exercising/glycolytic), and masseter (nonexercising/glycolytic). Ten-week-old male C57BL/6 mice were fed a high-fat diet (HFD) (45% fat) or standard CHOW diet (12% fat) ad libitum and underwent one of two training regimes: (1) constant-moderate training (END), or (2) high intensity interval training (HIIT) for 10 weeks (3 × 40 min sessions/week). Chow and HFD-fed untrained mice were used as control. Compared with Chow, HFD induced an increase in protein levels of low-molecular weight (LMW) adiponectin in gastrocnemius and masseter (~2-fold; P < 0.05), and a decrease of high-molecular weight adiponectin (HMW-most bioactive form) in quadriceps (~0.5-fold; P < 0.05). Only END prevented these changes (P < 0.05). HFD induced a decrease of adiponectin receptor 1 (AdipoR1) protein in exercising muscles of untrained mice (~0.5-0.8-fold; P < 0.05); notably, END also decreased AdipoR1 protein levels in lean and HFD mice. This type of training also normalized HFD-driven mRNA changes found in some adiponectin downstream factors (sirtuin 1, Pgc-1a, and Ucp2) in the three muscles tested. Our results indicate that diet, muscle type/activity, and exercise modality influences muscle adiponectin profile, and some of its mediators. These parameters should be taken into consideration when investigating this endocrine response of the skeletal muscle, particularly in the context of obesity and metabolic disorders.

Differential metabolic effects of constant moderate versus high intensity interval training in high-fat fed mice: possible role of muscle adiponectin.

Exercise regimens may have differing effects in the presence of obesity. In addition to being fat derived, adiponectin has recently been described as a myokine that regulates insulin sensitivity, which may link to exercise-related metabolic benefits in obesity. Whether skeletal muscle adiponectin varies in different exercise modalities is unclear. This study investigated the comparative effects of 10 weeks of endurance constant-moderate intensity exercise (END) with high intensity interval training (HIIT), on metabolic outcomes, including muscle adiponectin in a mouse model of diet-induced obesity. Ten-week-old male C57BL/6 mice were fed a high-fat diet (HFD) (45% FAT) or standard CHOW diet ab libitum and underwent one of three training regimes: (1) no exercise, (2) END, or (3) HIIT (8 bouts of 2.5 min with eight periods of rest of 2.5 min) for 10 weeks (3 × 40 min sessions/week). Chow-fed mice acted as controls. Compared with HFD alone, both training programs similarly protected against body weight gain (HFD = 45 ± 2; END = 37 ± 2; HIIT = 36 ± 2 g), preserved lean/fat tissue mass ratio (HFD = 0.64 ± 0.09; END = 0.34 ± 0.13; HIIT = 0.33 ± 0.13), and improved blood glucose excursion during an insulin tolerance test (HFD = 411 ± 54; END = 350 ± 57; HIIT = 320 ± 66 arbitrary units [AU]). Alterations in fasting glycemia, insulinemia, and AST/ALT ratios were prevented only by END. END, but not HIIT increased skeletal muscle adiponectin mRNA (14-fold; P < 0.05) and increased protein content of high molecular weight (HMW) adiponectin (3.3-fold), whereas HIIT induced a milder increase (2.4-fold). Compared with HFD, neither END nor HIIT altered circulating low (LMW) or high (HMW) molecular weight adiponectin forms. Furthermore, only END prevented the HFD downregulation of PGC1α (P < 0.05) mRNA levels downstream of muscle adiponectin. These data show that different training programs affect muscle adiponectin to differing degrees. Together these results suggest that END is a more effective regimen to prevent HFD-induced metabolic disturbances in mice.

Intramyocellular Lipid Droplet Size Rather Than Total Lipid Content is Related to Insulin Sensitivity After 8 Weeks of Overfeeding.

OBJECTIVE: Intramyocellular lipid (IMCL) is inversely related to insulin sensitivity in sedentary populations, yet no prospective studies in humans have examined IMCL accumulation with overfeeding. METHODS: Twenty-nine males were overfed a high-fat diet (140% caloric intake, 44% from fat) for 8 weeks. Measures of IMCL, whole-body fat oxidation from a 24-hour metabolic chamber, muscle protein extracts, and muscle ceramide measures were obtained before and after the intervention. RESULTS: Eight weeks of overfeeding did not increase overall IMCL. The content of smaller lipid droplets peripherally located in the myofiber decreased, while increases in larger droplets correlated inversely with glucose disposal rate. Overfeeding resulted in inhibition of Akt activity, which correlated with the reductions in smaller, peripherally located lipid droplets and drastic increases in ceramide content. Additionally, peripherally located lipid droplets were associated with more efficient lipid oxidation. Finally, participants who maintained a greater number of smaller, peripherally located lipid droplets displayed a better resistance to weight gain with overfeeding. CONCLUSIONS: These results show that lipid droplet size and location rather than mere IMCL content are important to understanding insulin sensitivity.

Utility and reliability of non-invasive muscle function tests in high-fat-fed mice.

NEW FINDINGS: What is the central question of this study? Non-invasive muscle function tests have not been validated for use in the study of muscle performance in high-fat-fed mice. What is the main finding and its importance? This study shows that grip strength, hang wire and four-limb hanging tests are able to discriminate the muscle performance between chow-fed and high-fat-fed mice at different time points, with grip strength being reliable after 5, 10 and 20 weeks of dietary intervention. Non-invasive tests are commonly used for assessing muscle function in animal models. The value of these tests in obesity, a condition where muscle strength is reduced, is unclear. We investigated the utility of three non-invasive muscle function tests, namely grip strength (GS), hang wire (HW) and four-limb hanging (FLH), in C57BL/6 mice fed chow (chow group, n = 48) or a high-fat diet (HFD group, n = 48) for 20 weeks. Muscle function tests were performed at 5, 10 and 20 weeks. After 10 and 20 weeks, HFD mice had significantly reduced GS (in newtons; mean ± SD: 10 weeks chow, 1.89 ± 0.1 and HFD, 1.79 ± 0.1; 20 weeks chow, 1.99 ± 0.1 and HFD, 1.75 ± 0.1), FLH [in seconds per gram body weight; median (interquartile range): 10 weeks chow, 2552 (1337-4964) and HFD, 1230 (749-1994); 20 weeks chow, 2048 (765-3864) and HFD, 1036 (717-1855)] and HW reaches [n; median (interquartile range): 10 weeks chow, 4 (2-5) and HFD, 2 (1-3); 20 weeks chow, 3 (1-5) and HFD, 1 (0-2)] and higher falls [n; median (interquartile range): 10 weeks chow, 0 (0-2) and HFD, 3 (1-7); 20 weeks chow, 1 (0-4) and HFD, 8 (5-10)]. Grip strength was reliable in both dietary groups [intraclass correlation coefficient (ICC) = 0.5-0.8; P < 0.05], whereas FLH showed good reliability in chow (ICC = 0.7; P < 0.05) but not in HFD mice after 10 weeks (ICC < 0.5). Our data demonstrate that non-invasive muscle function tests are valuable and reliable tools for assessment of muscle strength and function in high-fat-fed mice.

Skeletal muscle extracellular matrix remodeling after short-term overfeeding in healthy humans.

BACKGROUND: Skeletal muscle extracellular matrix (ECM) remodeling has been proposed as a feature of the pathogenic milieu associated with obesity and metabolic dysfunction. The aim of the current study was to examine the timeline of this response and determine whether 3 and 28days of overfeeding alters markers of ECM turnover. METHODS: Forty healthy individuals were overfed by 1250kcal/day for 28days. Hyperinsulinemic-euglycemic clamps and abdominal fat distribution were performed at baseline and day 28 of overfeeding and skeletal muscle biopsies taken at baseline, day 3 and day 28. mRNA expression (COL1a1, COL3a1, MMP2, MMP9, TIMP1, CD68, Integrin) was performed in 19 subjects that consented to having all biopsies performed and microarray analysis was performed in 8 participants at baseline and day 28. RESULTS: In the whole cohort, body weight increased by 0.6±0.1 and 2.7±0.3kg at days 3 and 28 (both P<0.001), respectively. Glucose infusion rate during the hyperinsulinemic-euglycemic clamp decreased from 54.8±2.8 at baseline to 50.3±2.5µmol/min/kg FFM at day 28 of overfeeding (P=0.03). Muscle COL1 and COL3 and MMP2 mRNA levels were significantly higher 28days after overfeeding (all P<0.05), with no significant changes in MMP9, TIMP1, CD68 and integrin expression. Microarray based gene set tests revealed that pathways related to ECM receptor interaction, focal adhesion and adherens junction were differentially altered. CONCLUSIONS: Skeletal muscle ECM remodeling occurs early in response to over-nutrition with as little as 3% body weight gain. Our findings contribute to the growing evidence linking muscle ECM remodeling and accumulation as another sequela of obesity-related insulin resistance.

Does weight cycling promote obesity and metabolic risk factors?

BACKGROUND: There remains common belief in the general community that weight cycling or 'yo-yo dieting' is associated with potential adverse effects on obesity and metabolic risk factors. In 1994, a review by the National Task Force on the Prevention and Treatment of Obesity concluded that weight cycling did not impact metabolism, and that weight loss attempts should not be discouraged. This study is an updated review of the literature published since 1994, to determine if weight cycling is associated with metabolic risk factors for obesity and type 2 diabetes. METHODS: A systematic literature search was conducted in PubMed, ISI Web of Science and SCOPUS to identify primary studies that examined weight cycling in relation to obesity and metabolic risk factors. Thirty-one studies with human subjects were retained. RESULTS: Fifty-eight percent (11/19) of publications reported that a history of weight cycling was correlated with increased body fat and central adiposity. Another fifty percent (4/8) of studies reported that the presence of weight cycling increased the likelihood of future weight gain, suggesting that weight cycling is potentially problematic for individuals attempting to lose weight. The majority of studies (13/17; 76%) did not show a detrimental effect of weight cycling on risk of type 2 diabetes. CONCLUSIONS: There is some evidence showing that weight cycling has no effect on risk of type 2 diabetes and inconclusive evidence that a history or presence of weight cycling influences body composition, or predisposes to future obesity. The available evidence so far suggests that there is little detrimental effect of weight cycling on current and future obesity and metabolic risk, and therefore weight loss efforts in individuals with overweight/obesity should continue to be encouraged.

Raised FGF-21 and Triglycerides Accompany Increased Energy Intake Driven by Protein Leverage in Lean, Healthy Individuals: A Randomised Trial.

A dominant appetite for protein drives increased energy intake in humans when the proportion of protein in the diet is reduced down to approximately 10% of total energy. Compensatory feeding for protein is apparent over a 1­2 d period but the mechanisms driving this regulation are not fully understood. Fibroblast growth factor-21 (FGF-21) has been identified as a candidate protein signal as levels increase in the circulation when dietary protein is low. The aim of this randomised controlled trial was to assess whether changes in percent dietary protein over a 4 d ad libitum experimental period in lean, healthy participants influenced energy intake, metabolic health, circulating FGF-21 and appetite regulating hormones including ghrelin, glucagon like peptide-1 and cholecystokinin. Twenty-two lean, healthy participants were fed ad libitum diets containing 10, 15 and 25% protein, over three, 4 d controlled, in-house experimental periods. Reduced dietary protein intake from 25% to 10% over a period of 4 d was associated with 14% increased energy intake (p = 0.02) as previously reported, and a 6-fold increase in fasting circulating plasma FGF-21 levels (p<0.0001), a 1.5-fold increase in serum triglycerides (p<0.0001), and a 0.9-fold decrease in serum total cholesterol (p = 0.02). Serum HDL cholesterol was reduced with a reduction in dietary protein from 15% to 10% (p = 0.01) over 4 d but not from 25% to 10% (p = 0.1) and the change from baseline was not different between diets. Plasma fasting insulin levels following the 4 d study period were significantly lower following the 25% ad libitum study period compared to the 15% protein period (p = 0.014) but not the 10% protein period (p = 0.2). Variability in interstitial glucose during each study period increased with a decrease in dietary protein from 25% to 15% and 10% (p = 0.001 and p = 0.04, respectively). Ghrelin, glucagon-like peptide-1 and cholecystokinin were unchanged. Increases in energy intake, plasma FGF-21 and serum triglycerides were associated with reductions in percent dietary protein from 25% to 10% energy over a 4 d ad libitum in-house feeding period and may be important in regulation of dietary protein intake. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12616000144415.

Energy Metabolic Adaptation and Cardiometabolic Improvements One Year After Gastric Bypass, Sleeve Gastrectomy, and Gastric Band.

CONTEXT: It is not known whether the magnitude of metabolic adaptation, a greater than expected drop in energy expenditure, depends on the type of bariatric surgery and is associated with cardiometabolic improvements. OBJECTIVE: To compare changes in energy expenditure (metabolic chamber) and circulating cardiometabolic markers 8 weeks and 1 year after Roux-en-y bypass (RYGB), sleeve gastrectomy (SG), laparoscopic adjustable gastric band (LAGB), or a low-calorie diet (LCD). Design, Setting, Participants, and Intervention: This was a parallel-arm, prospective observational study of 30 individuals (27 females; mean age, 46 ± 2 years; body mass index, 47.2 ± 1.5 kg/m2) either self-selecting bariatric surgery (five RYGB, nine SG, seven LAGB) or on a LCD (n = 9) intervention (800 kcal/d for 8 weeks, followed by weight maintenance). RESULTS: After 1 year, the RYGB and SG groups had similar degrees of body weight loss (33-36%), whereas the LAGB and LCD groups had 16 and 4% weight loss, respectively. After adjusting for changes in body composition, 24-hour energy expenditure was significantly decreased in all treatment groups at 8 weeks (-254 to -82 kcal/d), a drop that only persisted in RYGB (-124 ± 42 kcal/d; P = .002) and SG (-155 ± 118 kcal/d; P = .02) groups at 1 year. The degree of metabolic adaptation (24-hour and sleeping energy expenditure) was not significantly different between the treatment groups at either time-point. Plasma high-density lipoprotein and total and high molecular weight adiponectin were increased, and triglycerides and high-sensitivity C-reactive protein levels were reduced 1 year after RYGB or SG. CONCLUSIONS: Metabolic adaptation of approximately 150 kcal/d occurs after RYGB and SG surgery. Future studies are required to examine whether these effects remain beyond 1 year.